Immunoglobin heavy chain isotype switch recombination is a regulated process of DNA deletion, which joins a rearranged and expressed variable region to a new downstream constant region, deleting the DNA between. Each class of constant regions removes antigen in a different way, so the result of switch recombination is to alter how an immunoglobulin molecule removes antigen without altering its specificity for antigen. Switch recombination plays a critical role in the immune response, and impaired switch recombination can result in immunodeficiency disease. The proposed research will study the molecular mechanism of switch recombination. (1) We will determine the function of the GQN1 nuclease in switch recombination; (2) we will ask if transcription of the G-rich S region sequences causes G4 DNA structures to form; (3) we will ask how mutation of the B cell-specific factor, LR1, affects switch recombination; (4) we will determine the roles of the recombination/repair factors Rad52 and Rad51 in switch recombination; and (5) we will visualize the S regions in recombining B cells to identify dynamic interactions during switch recombination. These experiments will define the molecular components of the switch recombination pathway. Results of these experiments will also have broader implications, because molecules and mechanisms critical to switch recombination have more general roles in maintaining genomic stability in mammalian cells.